Design of novel polyphosphoesters (co)polymers for improving a drug delivery system based on calcium carbonate particles

Biomedical applications, especially drug delivery systems, often require biodegradable and biocompatible materials that permit safe retention as well as controlled delivery of a drug. CaCO3 particles are safe and biodegradable drug carriers that have excellent properties such as low density, high specific surface areas and porosity for drugs microencapsulation. The encapsulation of a model protein within CaCO3 particles has been successfully investigated by Boury and coworkers but the release profiles still need to be improved. In this project, we would like to slow down the kinetics of protein release. One strategy consists in loading the CaCO3 particles with degradable micelles containing the protein/drug in their core. In this perspective, we have developed a novel class of degradable polyphosphoesters (PPE) (co)polymers able to self-assemble into micelles. Note that the degradation products of PPEs, like phosphates, associated with calcium from the inorganic carrier could favor some reconstruction processes like bone regeneration. Pendant carboxylic acid functions were introduced along the backbone of the copolymers in order to increase their affinity for calcium and facilitate their incorporation in the CaCO3 particles.
First, an alkynyl-functionalized phospholane monomer, i.e. butynyl phosphate (BYP), was prepared by condensation of 2-chloro-2-oxo-1,3,2-dioxaphospholane and 3-butyn-1-ol (43 % yield), according to a reported procedure. Then, a series of well-defined (Ɖ < 1.2) alkyne-containing PBYP (co)polymers were synthesized by ring opening polymerization using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and thiourea (TU) as catalysts[5] (see scheme below). The structures of the PPE (co)polymers were characterized by 1H NMR, 31P NMR and size exclusion chromatography (SEC). Next, carboxylic acid functions were introduced along the PPE backbone by click-type thiol-yne addition of mercaptopropionic acid onto the pendant alkynes. The degradability of the PPEs was investigated at different pH. In the future, the self-assembly behavior of the PPE-based copolymers will be studied as well as their drug loading capacity and ability to accumulate within the CaCO3 particles. In addition, the acid-bearing PPE-based copolymers will be tested as templating agents for the synthesis of CaCO3 particles.